Silencing of exercise induced microRNA-501, microRNA-409 leads to aberrant neuronal homeostasis

Exercise has been shown to boost cognition in mammals. However, the underlying mechanism remain poorly understood. We hypothesized that circulating microRNAs may correlate to improved cognitive functions, particularly cognitive flexibility after exercise and could be critical for neurons functions. To address this, in our study, healthy human volunteers participated in an exercise paradigm coupled with various cognitive tests performed prior to and after exercise and high quality small RNAome data were generated from total blood collected at two time points (pre- and post-exercise). Advanced comparative computational approaches were employed to select candidate microRNAs and multiple functional experiments were designed to test effect of those candidates on neuronal transcriptome, and neuronal functions. Our analyses revealed a cluster of circulating microRNAs related to improved cognitive flexibility. After rigorous analyses, we selected two candidate microRNAs and inhibition of these microRNAs led to up-regulation of genes, conserved in increased stress responses and downregulation of genes related to synaptic morphology and functions. Functional data revealed that the two microRNAs are indeed critical for maintenance of neuronal functions and morphology. Newly discovered cluster of microRNAs shed light on the mechanism of exercise-improved cognition and the two candidate microRNAs are potential RNA therapeutic target against dementia. Primary hippocampal neurons were treated with anti-miR-409-5p and anti-miR-501-3p at DIV10. After 48 hours, cells were treated with trizol and RNA was isolated and subjected to RNA sequencing.